Granzymes, found in the cytoplasmic granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, are known to be critical for inducing target cell apoptosis during granule exocytosis-induced cytotoxicity. The observation that granzyme B can specifically cleave known sutoantigens has broad implications for its possible role in mediating the bypass of tolerance to autoantigens, and the subsequent development of autoinmune disease. It is hypothesized that granzymes- specifically granzyme B - are required for the initiation and propagation of autoimmune disease. This proposal outlines four Specific Aims designed to address the precise role of these proteases in the development of the autoimmune disease systemic lupus erythematosus (SLE). Immunological and biochemical methods, as well as animal models will be utilized to.test the hypothesis. Observations made in the SLE model system have the potential to be translated.to other autoimmune conditions for which changes induced during apoptosis are believed to contribute to the pathogenesis of disease.